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The acquisition of mesenchymal traits is considered a hallmark of breast cancer progression. However, the functional relevance of epithelial-to-mesenchymal transition (EMT) remains controversial and context dependent. Here, we isolate epithelial and mesenchymal populations from human breast cancer metastatic biopsies and assess their functional potential in vivo. Strikingly, progressively decreasing epithelial cell adhesion molecule (EPCAM) levels correlate with declining disease propagation. Mechanistically, we find that persistent EPCAM expression marks epithelial clones that resist EMT induction and propagate competitively. In contrast, loss of EPCAM defines clones arrested in a mesenchymal state, with concomitant suppression of tumorigenicity and metastatic potential. This dichotomy results from distinct clonal trajectories impacting global epigenetic programs that are determined by the interplay between human ZEB1 and its target GRHL2. Collectively, our results indicate that susceptibility to irreversible EMT restrains clonal propagation, whereas resistance to mesenchymal reprogramming sustains disease spread in multiple models of human metastatic breast cancer, including patient-derived cells in vivo.

Einleitung: Rheuma-VOR ist die größte Versorgungsforschungsstudie in Deutschland, mit dem Ziel, in vier Bundesländern drei entzündlich-rheumatische Erkrankungsbilder, die Rheumatoide Arthritis (RA), die Psoriasis Arthritis (PsA) und die axiale Spondyolarthritis (axSpA) möglichst[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Rheumatologiekongress 2021, 49. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 35. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Fluvial morphology is affected by a wide range of forcing factors, which can be external, such as faulting and changes in climate, or internal, such as variations in rock hardness or degree of fracturing. It is a challenge to separate internal and external forcing factors when they are co-located or occur coevally. Failure to account for both factors leads to potential misinterpretations. For example, steepening of channel network due to lithologic contrasts could be misinterpreted to be a function of increased tectonic displacements. These misinterpretations are enhanced over large areas, where landscape properties needed to calculate channel steepness (e.g. channel concavity) can vary significantly in space. In this study, we investigate relative channel steepness over the Eastern Carpathians, where it has been proposed that active rock uplift in the Southeastern Carpathians gives way N- and NW-wards to ca. 8 Myrs of post-orogenic quiescence. We develop a technique to quantify relative channel steepness, the relative steepness index, based on a wide range of concavities, and show that the main signal shows an increase in relative steepness index from east to west across the range. Rock hardness measurements and geological studies suggest this difference is driven by lithology. When we isolate channel steepness by lithology to test for ongoing rock uplift along the range, we find steeper channels in the south of the study area compared to the same units in the North. This supports interpretations from longer timescale geological data that active rock uplift is fastest in the southern Southeastern Carpathians.

Hintergrund: Der bevölkerungsbezogene und morbiditätsübergreifende Ansatz der Integrierten Versorgung „Gesundes Kinzigtal„ (IVGK) intendiert, die individuelle Versorgungsqualität und Patientenzufriedenheit zu verbessern sowie die Gesundheit der gesamten Kinzigtal-Bevölkerung[zum vollständigen Text gelangen Sie über die oben angegebene URL], 19. Deutscher Kongress für Versorgungsforschung (DKVF)

Hintergrund: Die Leberzirrhose ist eine chronische Krankheit, die sich über Jahrzehnte auf dem Boden verschiedener Risikofaktoren häufig unbemerkt entwickelt. Im Frühstadium der Leberzirrhose sind die Patienten in der Regel symptomfrei, es sind noch keine Organkomplikationen aufgetreten,[zum vollständigen Text gelangen Sie über die oben angegebene URL], 17. Deutscher Kongress für Versorgungsforschung (DKVF)

Hintergrund: Der Innovationsausschuss beim Gemeinsamen Bundesausschuss fördert die Evaluation der populationsbezogenen Integrierten Versorgung Gesundes Kinzigtal (IVGK). Das Einzugsgebiet der IVGK (Postleitzahlen 77709-77797, 78132) ist eine ländlich und kleinstädtisch geprägte Region,[zum vollständigen Text gelangen Sie über die oben angegebene URL], 17. Deutscher Kongress für Versorgungsforschung (DKVF)

International audience; Multiple acyl-CoA dehydrogenase deficiencies (MADDs) are a heterogeneous group of metabolic disorders with combined respiratory-chain deficiency and a neuromuscular phenotype. Despite recent advances in understanding the genetic basis of MADD, a number of cases remain unexplained. Here, we report clinically relevant variants in FLAD1, which encodes FAD synthase (FADS), as the cause of MADD and respiratory-chain dysfunction in nine individuals recruited from metabolic centers in six countries. In most individuals, we identified biallelic frameshift variants in the molybdopterin binding (MPTb) domain, located upstream of the FADS domain. Inasmuch as FADS is essential for cellular supply of FAD cofactors, the finding of biallelic frameshift variants was unexpected. Using RNA sequencing analysis combined with protein mass spectrometry, we discovered FLAD1 isoforms, which only encode the FADS domain. The existence of these isoforms might explain why affected individuals with biallelic FLAD1 frameshift variants still harbor substantial FADS activity. Another group of individuals with a milder phenotype responsive to riboflavin were shown to have single amino acid changes in the FADS domain. When produced in E. coli, these mutant FADS proteins resulted in impaired but detectable FADS activity; for one of the variant proteins, the addition of FAD significantly improved protein stability, arguing for a chaperone-like action similar to what has been reported in other riboflavin-responsive inborn errors of metabolism. In conclusion, our studies identify FLAD1 variants as a cause of potentially treatable inborn errors of metabolism manifesting with MADD and shed light on the mechanisms by which FADS ensures cellular FAD homeostasis.

Resumen basado en el de la publicación Título, resumen y palabras clave en inglés y español Resumen ampliado en español Se investigan métodos para estudiar las progresiones de aprendizaje de competencias de lecto-escritura utilizando evaluaciones basadas en escenarios. Interesa poder replicar las progresiones en el aprendizaje de la capacidad para argumentar en estudiantes de enseñanza secundaria obligatoria. Se recogen datos aplicando tres formas paralelas de una prueba que consiste en conjuntos de tareas basadas en escenarios con preguntas de distinto formato; cada estudiante respondió a dos de estas tres formas, que fueron asignadas aleatoriamente a cada uno de ellos. Aunque se han detectado algunas diferencias en las tareas de las formas paralelas, se ha encontrado un grado razonable de acuerdo entre las clasificaciones realizadas en base a las formas paralelas de la prueba. En general, se ha replicado empíricamente el orden de los niveles de la progresión en el aprendizaje de la argumentación, tal y como fueron asignados los niveles a las tareas de la prueba en el marco teórico. ESP